ABSTRACT This is an application for a K23 award for Dr. Richard Tsai, an Assistant Adjunct Professor of Neurology at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). Dr. Tsai's proposal to conduct clinical research on the clinical and imaging evolution of early progressive supranuclear palsy (ePSP) will help him achieve his goal of becoming an independent investigator and expert in neurodegenerative disease imaging and clinical trials methodology. This K23 will provide Dr. Tsai with the resources and support essential to accomplish the following goals: (1) to become an expert at patient-oriented clinical research in primary tauopathies such as PSP; (2) to advance his knowledge of clinical trials methodology and biostatistics; (3) to implement structural (volumetric MRI, diffusion tensor imaging) and molecular (tau positron emission tomography [PET]) imaging techniques in clinical studies and trials of primary tauopathies; (4) to develop an independent career in clinical research. To achieve these goals, Dr. Tsai has assembled a mentoring team of two primary mentors: Dr. Adam Boxer, director of the Alzheimer's Disease and Frontotemporal Dementia Clinical Trials Program and one of the world's experts in PSP, Dr. Gil Rabinovici, director of the MAC PET imaging program and one of the world's expert on molecular imaging in dementia. The mentoring team also includes two collaborators: Dr. Howard Rosen, a neurologist with expertise in neuroimaging in cognitive disorders and Dr. Iryna Lobach, a statistician who is an expert in study design and biostatistical analysis. There is an urgent need for effective therapy in neurodegenerative disease, and current experience indicates potential disease modifying therapies should begin in early stages of disease. The proposed research project will apply advanced structural MR imaging and molecular imaging techniques using novel tau PET ligands to evaluate the clinical evolution of ePSP. Dr. Tsai will characterize the clinical evolution ePSP, a new diagnostic category (Aim 1) and develop innovative imaging biomarkers using volumetric MRI, diffusion tensor imaging and tau PET imaging (Aim 2) that may one day be used as outcomes in therapeutic clinical trials. Additionally, Dr. Tsai will identify baseline signatures (Aim 3) of these imaging measures that may predict ePSP disease progression. This research will be a key step in a series of investigation that will develop longitudinal imaging biomarkers for PSP and other neurodegenerative disease in their early stages, and pave the way for the field to establish disease monitoring biomarkers useful for future clinical trials.